Maligancy-associated hypercalcemia (MAHC) is a common and important paraneoplastic syndrome. We have developed several independent criteria for subclassifying patients with MAHC according to two general mechanisms: humoral hypercalcemia of malignancy and local osteolytic hypercalcemia. The humoral syndrome appears to be extremely common, being identified in 80 percent of an initial series of 50 unselected patients with MAHC. The existing data base suggests that the humoral factor(s) has potent activity in the proximal renal tubule and in stimulating osteoclastic bone resorption but is not native parathyroid hormone (l-84). The proposed investigations constitute a broadly-based series of studies with three main objectives: l) to further characherize the humoral and local osteolytic syndromes in vivo, 2) to develop detection systems for and sources of the humoral material(s) in vitro, and 3) to develop an animal model of the human humoral syndrome. The in vivo studies call for further expansion of the data base in order to examine histopathologicl correlates, provide an appropriate framework for interpretation of the results of bone biopsy and measurements of circulating humoral substance, evaluate the implications of our existing findings in a prospective series of patients with squamous cell tumors, and provide a source of neoplastic tissue and cells for culture. Potential sources of the humoral material(s) in vitro include neoplastic tissue, culture cell lines, and tissue form animals with MAHC. Detection systems include a fetal bone resorbing system,the cytochemical bioassay for PTH, a canine renal cortical adenylyl cyclase system, and a hybridization system for probing neoplastic tissue or cells for the mRNA for pre-pro PTH. Existing animal models for MAHC will be examined, and an attempt to develop an animal model for the humoral syndrome will be made by transplanting cell lines into immunodeficient mice.